Functional analysis of RNF213 gene identified by genome-wide association study

• Project/Area Number: 23390267
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Pediatrics
• Research Institution: Tohoku University
• Principal Investigator: KURE Shigeo 東北大学, 医学(系)研究科(研究院), 教授 (10205221)
• Co-Investigator(Kenkyū-buntansha): TOMINGA Teiji 東北大学, 大学院・医学系研究科, 教授 (00217548)
• Project Period (FY): 2011-04-01 – 2014-03-31
• Project Status: Completed (Fiscal Year 2013)
• Budget Amount: ¥19,630,000 (Direct Cost: ¥15,100,000、Indirect Cost: ¥4,530,000); Fiscal Year 2013: ¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000); Fiscal Year 2012: ¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000); Fiscal Year 2011: ¥10,270,000 (Direct Cost: ¥7,900,000、Indirect Cost: ¥2,370,000)
• Keywords: 小児神経学 / モヤモヤ病 / 疾患感受性遺伝子 / RNF213遺伝子 / 血管内皮細胞 / 内頚動脈結紮 / ノックアウト・マウス / 発症機序

Research Abstract

Moyamoya disease (MMD) manifests progressive bilateral internal carotid artery stenosis and abnormal collateral vessels. A genome-wide association study was performed, which showed a strong association of RNF213 locus in chromosome 17q25-ter with MMD risk. Mutational analysis of RNF213 revealed a founder mutation in 73% of non-familial MMD cases and 1.4% of controls; carriers of this mutation have increased risk of MMD. We developed a genetic testing method for this founder mutation.To understand the function of RNF213 gene, we generated a knockout mice by gene targeting. Homozygous mice were born and grew normally and no abnormality was found in cerebral vascular development. The we ligated the internal carotid artery and observed reactive hypertrophy of vascular wall. The homozygous mice lacked the reactive hyperplasia of intima cells, which was constantly observed in wild-type mice, suggesting that Rnf213 gene plays a role in proliferation of intima cells.

Research Products

• [Journal Article] Development of a de novo arteriovenous malformation after bilateral revascularization surgery in a child with moyamoya disease (2014)
  • Author(s): Fujimura M, Kimura N, Ezura M, Niizuma K, Uenohara H, T ominaga T
  • Journal Title: J Neurosurg Pediatr Volume: (印刷中)
  • Peer Reviewed
• [Journal Article] Temporal profile of the vascular anatomy evaluated by 9.4-T magnetic resonance angiography and histopathological analysis in mice lacking RNF213 : a susceptibility gene for moyamoya disease (2014)
  • Author(s): Sonobe S, Fujimura M, Niizuma K, Nishijima Y, Ito A, Shimizu H, Kikuchi A, Arai-Ichinoi N, Kure S, T ominaga T
  • Journal Title: Brain Res Volume: 1552 Pages: 64-71
  • DOI: 10.1016/j.brainres.2014.01.011
  • Peer Reviewed
• [Journal Article] JAM Trial Investigators. Effects of extracranial-intracranial bypass for patients with hemorrhagic moyamoya disease : results of the Japan adult moyamoya trial (2014)
  • Author(s): Miyamoto S, Yoshimoto T, Hashimoto N, Okada Y, Tsuji I, Tominaga T, Nakagawara J, T akahashi JC
  • Journal Title: Stroke Volume: 45(5) Pages: 1415-21
  • Peer Reviewed
• [Journal Article] Efficacy of Superficial T emporal Artery-Middle Cerebral Artery Double Anastomoses in a Patient with Rapidly Progressive Moyamoya Disease : Case Report (2014)
  • Author(s): Yokosawa M, Hayashi T, Shirane R, Tominaga T
  • Journal Title: Neurol Med Chir (Tokyo)
  • NAID: 130004699228
• [Journal Article] Minocycline prevents focal neurological deterioration due to cerebral hyperperfusion after extracranial-intracranial bypass for moyamoya disease (2014)
  • Author(s): Fujimura M, Niizuma K, Inoue T, Sato K, Endo H, Shimizu H, T ominaga T
  • Journal Title: Neurosurgery Volume: 74(2) Issue: 2 Pages: 163-70
  • DOI: 10.1227/neu.0000000000000238
  • Peer Reviewed
• [Journal Article] IDH2 and TP53 mutations are correlated with gliomagenesis in a patient with Maffucci syndrome. (2014)
  • Author(s): Moriya K, Kaneko MK, Liu X, Hosaka M, Fujishima F, Sakuma J, Ogasawara S, Watanabe M, Sasahara Y, Kure S, Kato Y
  • Journal Title: Cancer Sci. Volume: 105 Issue: 3 Pages: 359-62
  • DOI: 10.1111/cas.12337
  • Peer Reviewed
• [Journal Article] Abdominal and lower back pain in pediatric idiopathic stabbing headache. (2014)
  • Author(s): Kakisaka Y, Ohara T, Hino-Fukuyo N, Uematsu M, Kure S
  • Journal Title: Pediatrics Volume: 133 Issue: 1 Pages: e245-e247
  • DOI: 10.1542/peds.2013-0793
  • Peer Reviewed
• [Journal Article] Moyamoya disease in pregnancy : a single institute experience (2013)
  • Author(s): Fujimura M, Akagi K, Uenohara H, T ominaga T
  • Journal Title: Neurol Med Chir (Tokyo) Volume: 53(8) Pages: 561-4
  • Peer Reviewed
• [Journal Article] Homozygous c. 14576G> A Variant of<I> RNF213</I> Predicts Early-Onset and Severe Form of Moyamoya Disease (2012)
  • Author(s): Miyatake S, Miyake N, Touho H, Nishimura-T, A, Kondo Y, Okada ; I, Tsurusaki ; Y, Doi H, Sakai H, Saitsu ; H, Shimojima K, Yamamoto T, Higurashi M, Kawahara, N, Kawauchi, H, Nagasaka, K, Okamoto N, Mori, T, Koyano S, Kuroiwa Y, Taguri M, Morita S, Matsuba S, Kure S, Matsumoto N
  • Journal Title: Neurology Volume: 78(11) Issue: 11 Pages: 803-10
  • DOI: 10.1212/wnl.0b013e318249f71f
  • Peer Reviewed
• [Journal Article] Temporal profile of de novo development of moyamoya vasculopathy in an adult : case report (2012)
  • Author(s): Shimoda Y, Fujimura M, Inoue T, Shimizu H, Tominaga T
  • Journal Title: Neurol Med Chir (Tokyo) Volume: 52(5) Pages: 339-42
  • NAID: 10030314630
  • Peer Reviewed
• [Journal Article] Lessons learned from moyamoya disease : outcome Lessons learned from moyamoya disease: outcome (2012)
  • Author(s): Fujimura M, Tominaga T
  • Journal Title: Neurol Med Chir (Tokyo) Volume: 52(5) Pages: 327-32
  • Peer Reviewed
• [Journal Article] Efficacy of prophylactic blood pressure lowering according to a standardized postoperative management protocol to prevent symptomatic cerebral hyperperfusion after direct revascularization surgery for moyamoya disease (2012)
  • Author(s): Fujimura M, Inoue T, Shimizu H, Saito A, Mugikura S, Tominaga T
  • Journal Title: Cerebrovasc Dis Volume: 33(5) Issue: 5 Pages: 436-45
  • DOI: 10.1159/000336765
  • Peer Reviewed
• [Journal Article] Mutations in genes encoding the glycine cleavage system predispose to neural tube defects in mice and humans (2012)
  • Author(s): Narisawa A
  • Journal Title: Hum Mol Genet Volume: 21 Issue: 7 Pages: 1496-1503
  • DOI: 10.1093/hmg/ddr585
  • Peer Reviewed
• [Journal Article] Hypoperfusion in caudate nuclei in patients with brain-lung-thyroid syndrome (2012)
  • Author(s): Uematsu M
  • Journal Title: J Neurol Sci Volume: 315 Issue: 1-2 Pages: 77-81
  • DOI: 10.1016/j.jns.2011.11.025
  • Peer Reviewed
• [Journal Article] Paradoxical increase in seizure frequency with valproate in nonketotic hyperglycinemia (2012)
  • Author(s): Tsuyusaki Y
  • Journal Title: Brain Dev Volume: 341 Issue: 1 Pages: 72-75
  • DOI: 10.1016/j.braindev.2011.01.005
  • Peer Reviewed
• [Presentation] Identification of a susceptibility gene for Moyamoya disease (2013)
  • Author(s): Kure S
  • Organizer: Kure S in 3rd Inetrnational Moyamoya disease Meeting
  • Place of Presentation: Sapporo, Japan
  • Invited
• [Presentation] Diagnosis of Moyamoya Disease; Revisit of Suzuki's Angiographic Grading (2013)
  • Author(s): Tominaga T
  • Organizer: Tominaga T in 3rd Inetrnational Moyamoya disease Meeting
  • Place of Presentation: Sapporo, Japan
  • Invited
• [Presentation] Identification of a susceptibility gene for Moyamoya disease (2012)
  • Author(s): Kure S
  • Organizer: Kure S Genetics and Genomics of Vascular Disease Workshop II in NAVBO Workshops in V ascular Biology 2012
  • Place of Presentation: in Pacific Grove, CA, Monterey
  • Invited
• [Presentation] Identification of a susceptibility gene for Moyamoya disease in Japanese patients with Moyamoya disease and its clinical significance (2012)
  • Author(s): Kure S, Kamada F , Aoki Y , Abe Y , Kikuchi A, Komatsuzaki S, Kanno J, Matsubara Y , T ouho H, Miyatake S, Matsumoto N
  • Organizer: 54 th Annual meeting of Society of Child Neurology
  • Place of Presentation: Sapporo, Japan
• [Presentation] モヤモヤ病の疾患感受性遺伝子の同定 (2011)
  • Author(s): 呉 繁夫
  • Organizer: 第53回日本神経学会総会
  • Place of Presentation: 横浜
• [Presentation] モヤモヤ病遺伝的要因の解明-疾患感受性遺伝子と創始者変異の同定 (2011)
  • Author(s): 呉 繁夫, 鎌田文顕, 青木洋子, 阿部裕, 新堀哲也, 小松崎匠子, 菊池敦生, 菅野潤子, 土屋滋, 松原洋一
  • Organizer: 第114回日本小児科学会学術集会
  • Place of Presentation: 東京
• [Book] Health Labour Sciences Research Grant for Research on Measures for Infractable Diseases. Guidelines for diagnosis and treatment of moyamoya disease (spontaneous occlusion of the circle of Willis). Neurol Med Chir (Tokyo) (2012)
  • Author(s): Tominaga T
  • Publisher: Research Committee on the Pathology and Treatment of Spontaneous Occlusion of the Circle of Willis